Although the occurrence of new cases of gastric cancer has diminished in the recent years, gastric cancer is still one of the most common malignancies. In Finland, appr. 250 to 300 new cases of cancer/one million people/year are registered. In the age group of people above 50, there are an estimated 2350 cases of stomach cancer, which is about 3 per mille of the age group population (Finnish Cancer Registry—The Institute for Statistical and Epidemiological Cancer Research 1993). In addition to Finland, there is a high gastric cancer incidence in Iceland, South America and especially in Japan and China.
The prognosis of gastric cancer is usually poor, as there is no specific treatment. Presently the only possibility of successfully treating gastric cancer is its early detection and total removal surgically.
Gastric cancer does not necessarily give any symptoms in its early stages. The late appearance of symptoms naturally delays the patient from seeking treatment. On the other hand, the clinical findings in the early stage of gastric cancer are often non-specific. The primary diagnostic method for gastric cancer is presently gastroscopy and biopsies, cell and aspiration cytology associated therewith. As routine gastroscopies are carried out in order to examine symptoms, such as pain in the upper abdomen or bleeding of the gastrointestinal tact, a symptomatic gastric cancer discovered in this manner is often already far advanced and thus inoperable. Attempts have also been made at improving primary diagnostics with various immunological methods, but no sufficiently specific immunological method has been successfully developed.
It is a primary object to find the means by which it would be possible to identify within the general population easily and with moderate costs those persons which might be suffering from gastric cancer in its initial stages. After identification these persons should immediately be examined by gastroscopy. At the same time those persons could be identified which exhibit premalignant gastric changes which need to be followed up.
Gastric cancer can be preceded by a number of different gastric diseases or conditions (so called precancerous conditions), which are chronic atrophic gastritis, pernicious anaemia, ventricular ulcer, gastric polyposis and the Ménétrier disease (giant hypertrophic gastritis). Clearly identifiable changes of the mucosa are dysplasia and adenoma. The said conditions are associated with an appr. 4 to 5 fold relative cancer risk, as compared to the general population. It has been established that in almost all diseases the risk is mediated over chronic atrophic gastritis.
Chronic gastritis means a prolonged inflammatory condition of the gastric mucosa. The disease can coarsely be divided into the so-called superficial and the atrophic form. In superficial gastritis, the inflammatory cell infiltration is concentrated below the surface epithelium. In case the inflammation progresses and diffuses between the specific gastric secretory glands, one refers to chronic atrophic gastritis. In such a case, the normal glandular structures of the gastric mucosa are at least partly substituted by metaplastic changes.
The relative risk of gastric cancer in patients suffering from atrophic gastritis in the corpus area of the stomach, has been estimated, as calculated from the Finnish cancer statistics, to be about 4- to 5-fold as compared to persons having a healthy mucosa. In addition, there is a risk for falling ill with pernicious anaemia due to intrinsic factor deficiency and B12 vitamin absorption disturbance. In severe atrophy of the antrum area, the risk is even 18-fold. If atrophic changes appear both in the antrum and the corpus area (pangastritis), the risk can increase to even 90-fold (Sipponen, P, Kekki, M, Haapakoski, J. Ihamäki, T & Siurala, M (1985) Gastric cancer risk in chronic atrophic gastritis: statistical calculations of cross-sectional data Int J Cancer 35:173-77).
Helicobacter pylori is a spiral shaped, gram-negative bacterium which thrives in the mucus in the immediate vicinity of the surface epithelial cells of the gastric mucosa and in the cell interstices. The bacterium apparently is transmitted perorally from one person to the other. The effect of the bacterium on the gastric mucosa is an inflammation reaction, which is mediated over a complement by liberating strong inflammation mediator substances. After the acute stage, the inflammation is transformed into chronic gastritis. In patients suffering from chronic gastritis, in 70 to 90% a Helicobacter pylori infection can be established (Calam, J (1994) Helicobacter pylori (Review) Eur. J. Clin Invest 24: 501-510). As Helicobacter pylori infection and chronic gastritis in the stomach are closely associated, it has been stipulated that this bacterial infection could be one etiological factor in the development of stomach cancer. It is for this reason possible that eradication of the Helicobater pylori bacteria in the initial stages of the infection, could prevent the development of atrophy associated with chronic gastritis, and thus reduce the cancer risk and the risk of peptic ulcers.
The publication WO 96/15456, which is included herein for reference, discloses a method for screening for the risk of cancer by determining the concentration of the analytes pepsinogen I and gastrin-17 from a serum sample of a subject. According to the said publication, the so determined concentration values are then compared to a cut-off value and a reference value for each analyte. A serum pepsinogen I concentration below the cut-off value for pepsinogen I in combination with a gastrin-17 concentration value above the upper reference limit indicates severe atrophy of the corpus area of the stomach. A serum gastrin-17 level below the cut-off value for gastrin-17 in combination with a pepsinogen I value above the cut-off value for pepsinogen I on the other hand indicates atrophy of the antrum area of the stomach. In case the serum pepsinogen I is below the cut-off value for pepsinogen I and the gastrin-17 level is at the lower limit of its reference value, this is an indication of severe atrophy in the whole stomach, i.e. of atrophic pangastritis.
According to an embodiment disclosed, the said tests may be combined with a test for Helicobacter pylori antibodies.
According to the said WO-publication, the method can be supplemented with a so-called protein stimulation test, according to which a blood sample is taken in the morning after fasting, whereafter the patient eats a protein-rich standard meal and blood samples are taken at 15 minute intervals for two hours. The maximal increase is evident after appr. 20 minutes. In case the atrophy is located in the antrum, there will be a strongly reduced response in this test. When the atrophy is located in the corpus, the response will be normal or increased, whereas atrophy of the whole mucosa leads to a reduced response.
The WO-publication WO 00/67035, which is included herein for reference, discloses a method for assessing the risk of peptic ulcer by determining quantitatively the concentration of serum pepsinogen I and serum gastrin-17. According to this method, if both the measured pepsinogen I and gastrin-17 values are high, above the upper limit of their respective reference values, or the serum pepsinogen I value is above the upper limit of its reference value in combination with a gastrin-17 value within the reference range or below its cut-off value, this is an indication of an increased risk of peptic ulcer.
Methods are known in the art for measuring the concentrations of the various analytes, and there are also commercially available kits for this purpose. Some exemplatory methods for carrying out the said determinations are described in the WO-publication 96/15456 as well.